Any deviation between treated and planned volume for 3-D conformal therapy, such as IMRT, may cause an adverse clinical outcome. It is therefore critical to minimize all potential deviations using an on-board (or real- time) procedure immediately prior to radiation delivery. At present, conventional 2-D radiographic imaging and state-of-the-art 3-D cone-beam CT (CBCT) are typically employed for treatment verification. However, 2-D radiographic verification is mainly based on bony structures and/or implanted fiducials, and is sub-optimal for soft-tissue targets. While on-board CBCT can provide 3-D soft tissue information, it has three major limitations: 1) The acquisition time is limited to 60 seconds (~15 breathing cycles) for on-board CBCT, makes single breath- hold imaging impractical for organs which exhibit respiratory motion; 2) 360o mechanical clearance for CBCT acquisition may limit the use of CBCT for large patients, those with tumors at peripheral locations (e.g. breast), or those with substantial immobilization or support devices; 3) A high radiation dose (2-9 cGy) is delivered to the imaged volume with current imaging techniques, which is undesirable for daily imaging and may be a particular problem for those who are at high risk of developing second malignancies. To overcome these limitations, we propose an innovative digital tomosynthesis (DTS) imaging technology for 3-D target localization. Although DTS technology has been used for digital chest and mammography, its use in target localization is unknown. DTS only requires limited gantry rotation (e.g., a scan angle of 40o or less) to reconstruct 3-D anatomic information. Thus, imaging time and dose are substantially reduced compared to CBCT, making breath-hold DTS a simple solution for daily imaging of moving organs. Further, the reduced mechanical clearance needed for DTS makes it more widely applicable than CBCT. At present, the localization accuracy using DTS technology in treatment verification remains unknown. This proposal hypothesizes that the target localization accuracy using DTS technology is better than 2-D radiographs and is comparable to CBCT but with less imaging time and dose, and better mechanical clearance. To validate this hypothesis, Aim #1 is intended to determine optimal DTS scan angles for 4 anatomic sites: head and neck, thorax, abdomen, and pelvis. A small scan angle is desirable for imaging efficiency but less desirable for image quality. Therefore, we will assess the impact of scan angle on (a) the DTS contrast-to-noise ratio and resolution in phantoms and (b) the mutual information shared between DTS and CBCT slices, using patient data from the 4 anatomic sites. In Aim #2, we will then quantitatively compare DTS- based target localization accuracy to that of 2-D radiographs and CBCT using patient data from the 4 anatomic sites. To achieve this goal, three physicians will measure relative shifts and rotations between reference and on- board images using 2-D, DTS, CBCT technologies. We anticipate that the DTS target localization accuracy will be equivalent to CBCT and an improvement over 2-D radiographic imaging. Yet, we expect DTS to be more practical, more efficient, and deliver lower dose than full CBCT for daily 3-D target localization. Accurate alignment of the radiation-therapy beam with the tumor target is essential for removing the tumor and for sparing surrounding healthy tissue. Currently, on-board cone-beam CT (CBCT) is the best method for aligning soft-tissue tumor, such as tumor in the breasts, lungs, or lower abdomen, yet use of CBCT in target localization in radiation therapy is restricted by its long acquisition time, its demanding mechanical clearance requirements, and its high radiation dose. Some are difficult to improve because there is a limitation of gantry rotation speed for conventional linear accelerators. The digital tomosynthesis (DTS) approach that we propose will provide more widely and more routinely applicable alignment of soft tissue, via much shorter acquisition time, much less mechanical constraint, and much lower radiation dose. This more frequent and broader range of application will translate into more consistent elimination of tumor and into less damage to nearby healthy tissue. [unreadable] [unreadable] [unreadable]